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Title: BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

Abstract

Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure–activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure–activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NSFNIHOTHER
OSTI Identifier:
1373795
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 12
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Ayoub, Alex M., Hawk, Laura M. L., Herzig, Ryan J., Jiang, Jiewei, Wisniewski, Andrea J., Gee, Clifford T., Zhao, Peiliang, Zhu, Jin-Yi, Berndt, Norbert, Offei-Addo, Nana K., Scott, Thomas G., Qi, Jun, Bradner, James E., Ward, Timothy R., Schönbrunn, Ernst, Georg, Gunda I., and Pomerantz, William C. K. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.6b01336.
Ayoub, Alex M., Hawk, Laura M. L., Herzig, Ryan J., Jiang, Jiewei, Wisniewski, Andrea J., Gee, Clifford T., Zhao, Peiliang, Zhu, Jin-Yi, Berndt, Norbert, Offei-Addo, Nana K., Scott, Thomas G., Qi, Jun, Bradner, James E., Ward, Timothy R., Schönbrunn, Ernst, Georg, Gunda I., & Pomerantz, William C. K. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen. United States. doi:10.1021/acs.jmedchem.6b01336.
Ayoub, Alex M., Hawk, Laura M. L., Herzig, Ryan J., Jiang, Jiewei, Wisniewski, Andrea J., Gee, Clifford T., Zhao, Peiliang, Zhu, Jin-Yi, Berndt, Norbert, Offei-Addo, Nana K., Scott, Thomas G., Qi, Jun, Bradner, James E., Ward, Timothy R., Schönbrunn, Ernst, Georg, Gunda I., and Pomerantz, William C. K. Tue . "BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen". United States. doi:10.1021/acs.jmedchem.6b01336.
@article{osti_1373795,
title = {BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen},
author = {Ayoub, Alex M. and Hawk, Laura M. L. and Herzig, Ryan J. and Jiang, Jiewei and Wisniewski, Andrea J. and Gee, Clifford T. and Zhao, Peiliang and Zhu, Jin-Yi and Berndt, Norbert and Offei-Addo, Nana K. and Scott, Thomas G. and Qi, Jun and Bradner, James E. and Ward, Timothy R. and Schönbrunn, Ernst and Georg, Gunda I. and Pomerantz, William C. K.},
abstractNote = {Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure–activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure–activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.},
doi = {10.1021/acs.jmedchem.6b01336},
journal = {Journal of Medicinal Chemistry},
number = 12,
volume = 60,
place = {United States},
year = {Tue Jun 06 00:00:00 EDT 2017},
month = {Tue Jun 06 00:00:00 EDT 2017}
}